The objective of this research grant is to characterize the mechanisms for the differences between two strains of rats which differ in their susceptibility to obesity when eating a high fat diet. The Osborne- Mendel rat (OM) rapidly becomes obese when maintained on a high fat diet while the S5B/PI (S5B) rat remains lean when eating the same diet. We have recently demonstrated that the OM rat increases its intake of a high fat diet after administration of the 5-HT1A agonist, 8-hydroxy-2- (di-n-proplyamino)tetralin, which inhibits serotonin synthesis and release. S5B rats do not increase food intake after this treatment. In addition, fenfluramine treatment prevents high fat diet-induced obesity in the OM rat. This proposal focuses on the mechanisms underlying two aspects of this dietary-induced obesity. Our first aim will be to elucidate the central nervous system neurotransmitter signals that mediate fat preference by examining the serotonin system in these two rat strains. We will test the hypothesis that the serotonergic system is more active in the S5B rat than the OM rat. The first three experiments in this aim will investigate the effects on food intake in OM and S5B rats by altering serotonin levels in the paraventricular nucleus. The next five experiments will determine the contribution of the dorsal raphe nucleus to the serotonin systems in OM and S5B rats. The last two experiments will examine the hypothesis that opioids in the hindbrain may modulate the serotonergic signals from the paraventricular nucleus. We will utilize the novel technique of central antisense oligonucleotide application in two critical experiments to test these systems. The second aim will examine the difference in peripheral signaling systems that responds to nutrient infusion in these two rat strains. We will test the hypothesis that fatty acids in the GI tract activate vagal mechanisms more effectively int the S5B rat. We have already demonstrated that S5B rats are much more sensitive to the satiating effects of intraintestinal fat infusions. There are seven experiments proposed which will examine the involvement of the vagus nerve, cholecystokinin, glutamate, c-fos activated neurons and serotonin in the differential responsiveness to nutrient infusion in OM and S5B rats. Our laboratory has made significant advances toward understanding dietary-induced obesity. We now propose these well founded, important and exciting studies which will provide critical new insights into anatomical, physiological and molecular mechanisms by which high levels of dietary fat induce obesity.